Phenylacetic acid compounds

ABSTRACT

The present invention provides a process for the preparation 6-[3-(hetero)aryloxy-2-fluoro-benzyl]-2H-pyridazin-3-one compounds 1 where R2 is an optionally substituted aryl or an optionally substituted heteroaryl, R 6  is NO 2 , NH 2 , alkyl, halogen, or a function group readily derived therefrom and R 4c  is  
                 
 
hydrogen or alkyl. There also is provided a process for the preparation of phenylacetic acid compounds 2, wherein R 2  and R 6  are as defined previously and R 5a  is hydrogen or alkyl, which are useful for the preparation of pyridazinone compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Ser. No.60/562,650 filed Apr. 15, 2004, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of6-(2-fluoro-3-(hetero)aryl-benzyl)-4-alkyl-2H-pyridazin-3-one (1; R^(4c)is alkyl) and 6-(2-fluoro-3-(hetero)aryloxy-benzyl)-2H-pyridazin-3-onecompounds (1; R^(4c) is hydrogen) compounds where R¹, R², R^(4a), R^(4c)and R⁶ are defined below. The invention also relates to compoundsaccording to formula 2 wherein R¹ is CH₂CO₂R^(4a),CH(CO₂R^(4a))CO₂R^(4a) or 3 which are useful for the preparation of 1.The 2H-pyridazin-3-one compounds 1 inhibit human immunodeficiency virus(HIV) reverse transcriptase and are useful for treatment of individualsinfected with HIV.

BACKGROUND OF THE INVENTION

Pyridazinones are components of numerous pharmacologically diversecompounds. Thyroxin analogs have been reported, which contain, interalia, the pyridazinone ring, and these analogs were reported to lowerplasma cholesterol without the cardio-stimulatory effect of thyroxine(A. H. Underwood et al. Nature 1986 324(6096):425-429; P. D. Leeson etal. J. Med Chem 1989 32(2):320-326 and P. D. Leeson et al. EP 0188351).Oxo-pyridazinylmethyl substituted tyrosines that are selectiveantagonists for the haematopoietic phosphatase SH2 domain have beenreported (D. J. Dunnington, WO9624343, WO 9702023 and WO9702024).WO2001085670 (H. Shiohara et al.) discloses relatedpyridazinone-containing malonamide derivatives useful for treatingcirculatory diseases. EP 810218 (D. A. Allen et al.) discloses benzoylsubstituted benzyl-pyridazinone compounds which are cyclooxygenaseinhibitors and potential antiinflammatory or analgesic compounds. U.S.Ser. No. 60/457,144 (J. P. Dunn et al.), hereby incorporated byreference in its entirety, discloses pyridazinone compounds useful toinhibit HIV reverse transcriptase.

The pyridazinone ring can be introduced into a molecule by alkylation ofa phenyl acetic acid derivative 4 (R═CO₂R^(4a)) or a phenylacetonitrile4 (R═CN) with 3,6-dichloropyrazine (5a; M. M. Rodgers and J. P. English,U.S. Pat. No. 2,371,086). Acid- or based catalyzed hydrolysis of theester or nitrile 6 (R═CN or COR^(4a)) affords the correspondingcarboxylic acid which can be isolated if desired, or subjected toacid-catalyzed decarboxylation in situ. Hydrolysis of thechloropyridazine affords the pyridazinone 7. (P. D. Leeson and J. C.Emmett, J. Chem. Soc. Perkin I 1988 3085; D. A. Allen et al., EP810218). While this process is often satisfactory with 5a wherein bothchlorine carbon bonds are chemically equivalent, unsymmetricaldichloropyridazinones such as 5b (R^(a)=alkyl) produce a mixture ofregioisomers which are often difficult to separate. Alternately,pyridazinones are formally equivalent to 4-oxo-butenoic acid amides andan appropriately substituted 4-oxo-butenoic acid derivative can beconverted to pyridazinones by exposure to hydrazine hydrate.

The present process affords a convenient alternate route to4-alkylpyridazinones 7 (Ra=alkyl) in which the regioisomer problemcreated by the alkyl substituent is conveniently resolved in an earlyconvergent step in the process. The present invention further affords aconvenient route tro 3-(hetero)aryloxy-2-fluoro-phenylacetic acidcompounds which are useful intermediates to prepare HIV reversetranscriptase inhibitors. Moreover, the present process permits theregiospecific elaboration of four contiguous aryl carbons.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

In general, the nomenclature used in this application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

The term “alkenyl” as used herein denotes an unsubstituted hydrocarbonchain radical having from 2 to 10 carbon atoms having one or two doublebonds. The term “lower alkenyl” denotes an unsubstituted hydrocarbonchain radical containing 1 to 6 carbon atoms and having one or twodouble bonds. “C₂₋₁₀ alkenyl” as used herein refers to an alkenylcomposed of 2 to 10 carbons. Examples are vinyl, 1-propenyl, 2-propenyl(allyl) or 2-butenyl (crotyl).

The term “haloalkyl” as used herein denotes a unbranched or branchedchain alkyl group as defined above wherein 1, 2, 3 or more hydrogenatoms are substituted by a halogen. Examples are 1-fluoromethyl,1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl,trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl,1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl,2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or2,2,2-trifluoroethyl.

The term “cycloalkyl” as used herein denotes a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₈ cycloalkyl” asused herein refers to an cycloalkyl composed of 3 to 8 carbons in thecarbocyclic ring.

The term “alkoxy group” as used herein means an —O-alkyl group, whereinalkyl is as defined above such as methoxy, ethoxy, n-propyloxy,i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy,including their isomers. “Lower alkoxy” as used herein denotes an alkoxygroup with a “lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy”as used herein refers to an —O-alkyl wherein alkyl is C₁ .

The term “alkylthio” or “thioalkyl” means an —S-alkyl group, whereinalkyl is as defined above such as meththio, ethylthio, n-propylthio,i-propylthio, n-butylthio, hexylthio, including their isomers. “Loweralkylthio” or “lower thioalkyl” as used herein denotes an alkylthiogroup with a “lower alkyl” group as previously defined. “C₁₋₁₀alkylthio” as used herein refers to an —S-alkyl wherein alkyl is C₁₋₁₀.

The terms “alkylsulfinyl” and “arylsulfinyl” as used herein denotes agroup of formula —S(═O)R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein denotes agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein.

The term “haloalkoxy” as used herein denotes a —O-(haloalkyl) group,wherein haloalkyl is as defined herein. Examples of haloalkoxy groupsare difluoromethoxy, 2,2,2-trifluoroethoxy, 3-chloropropyloxy. The term“haloalkylthio” as used herein denotes a —S-(haloalkyl) group.

The term “halogen” or “halo” as used herein denotes fluorine, chlorine,bromine, or iodine.

The terms “amino”, “alkylamino” and “dialkylamino” as used hereindenotes —NH₂, —NHR and —NR₂ respectively and R is alkyl as definedabove. The two alkyl groups attached to a nitrogen in a dialkyl moietycan be the same or different. The terms “aminoalkyl”, “alkylaminoalkyl”and “dialkylaminoalkyl” as used herein refer to NH₂(CH₂)_(n)—,RHN(CH₂)_(n)—, and R₂N(CH₂)_(n)— respectively wherein n is 1 to 6 and Ris alkyl as defined above. “C₁₋₁₀ alkylamino” as used herein refers toan-aminoalkyl wherein alkyl is C₁₋₁₀.

The term “acylamino” as used herein denotes a group of formula —NHC(═O)Rwherein R is hydrogen, lower alkyl as defined herein.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The terms “alkoxycarbonyl” and “aryloxycarbonyl” as used herein denotesa group of formula —C(═O)OR wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein.

The prefix “carbamoyl” as used herein denotes the radical —CONH₂. Theprefix “N-alkylcabamoyl” and “N,N-dialkylcarbamoyl” means a the radicalCONHR′ or CONR′R″ respectively wherein the R′ and R″ groups areindependently alkyl as defined herein. The prefix N-arylcabamoyl”denotes the radical CONHR′ wherein R′ is an aryl radical as definedherein.

The term “polar aprotic solvent” means organic solvents such asformamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidoneor hexamthylphosphoramide.

The term “ethereal solvent” means solvents such as tetrahydrofuran,dimethoxyethane, dioxane, and dialkyl ethers such as diethyl ether andmethyl isobutyl ether.

The term “aryl” as used herein denotes a monovalent aromatic carbocyclicradical containing 5 to 15 carbon atoms consisting of one individualring, or one or more fused rings in which at least one ring is aromaticin nature, which can optionally be substituted with one or more,preferably one or three substituents independently selected fromhydroxy, thio, cyano, alkyl, alkoxy, lower haloalkoxy, alkylthio,halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino,alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl,arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl,alkylcarbamoyl and dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino,arylcarbonylamino, unless otherwise indicated. Alternatively twoadjacent atoms of the aryl ring may be substituted with a methylenedioxyor ethylenedioxy group. Examples of aryl radicals include, but are notlimited to, phenyl, naphthyl, indanyl, anthraquinolyltetrahydronaphthyl, 3,4-methylenedioxyphenyl,1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroisoquinoline-7-yl,and the like. The term “(hetero)aryl” is used to indicate that the ringsubstituent can be either an aryl or a heteroaryl ring.

The term “aryloxy” as used herein denotes a O-aryl group, wherein arylis as defined above. An aryloxy group can be unsubstituted orsubstituted with one or two suitable substituents. The term “phenoxy”refers to an aryloxy group wherein the aryl moiety is a phenyl ring. Theterm “heteroaryloxy” as used herein means an —O-heteroaryl group,wherein heteroaryl is as defined below. The term “(hetero)aryloxy” isuse to indicate the moiety is either an aryloxy or heteroaryloxy group.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing four to eight atoms per ring, incorporating oneor more N, O, or S heteroatoms, the remaining ring atoms being carbon,with the understanding that the attachment point of the heteroarylradical will be on an aromatic ring. As well known to those skilled inthe art, heteroaryl rings have less aromatic character than theirall-carbon counter parts. Thus, for the purposes of the invention, aheteroaryl group need only have some degree of aromatic character.Examples of heteroaryl moieties include monocyclic aromatic heterocycleshaving 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is notlimited to, pyridinyl, pyridazinone, pyrimidinyl, pyrazinyl, pyrrolyl,pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole,triazoline, thiadiazole and oxadiaxoline which can optionally besubstituted with one or more, preferably one or two substituentsselected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy,alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen,amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino andarylcarbonylamino. Examples of bicyclic moieties include, but are notlimited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. Bicyclicmoieties can be optionally substituted on either ring. The term(hetero)aryl is used to indicate that the ring substituent can be eitheran aryl or a heteroaryl ring.

As used herein, the term “treating”, “contacting” or “reacting” whenreferring to a chemical reaction means to add or mix two or morereagents under appropriate conditions to produce the indicated and/orthe desired product. It should be appreciated that the reaction whichproduces the indicated and/or the desired product may not necessarilyresult directly from the combination of two reagents which wereinitially added, i.e., there may be one or more intermediates which areproduced in the mixture which ultimately leads to the formation of theindicated and/or the desired product.

The term “optional” or “optionally” as used herein means that thesubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “aryl groupoptionally mono- or di-substituted with an alkyl group” means that thealkyl may but need not be present, and the description includessituations where the aryl group is mono- or disubstituted with an alkylgroup and situations where the aryl group is not substituted with thealkyl group.

The term “alkali metal” refers to a group I metal including, but notlimited to lithium (Li⁺), sodium (Na⁺) or potassium (K⁺). One skilled inthe art will be aware that while these alkali metals are commonly used,other cations such as magnesium (Mg²⁺) may be used without departingfrom the spirit of the invention.

Abbreviations used in this application include: acetyl (Ac), acetic acid(HOAc), azo-bis-isobutyrylnitrile (AIBN), 1-N-hydroxybenzotriazole(HOBT), atmospheres (Atm), high pressure liquid chromatography (HPLC),9-borabicyclo[3.3.1]nonane (9-BBN or BBN), methyl (Me),tert-butoxycarbonyl (Boc), acetonitrile (MeCN), di-tert-butylpyrocarbonate or boc anhydride (BOC₂O),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),benzyl (Bn), m-chloroperbenzoic acid (MCPBA), butyl (Bu), methanol(MeOH), benzyloxycarbonyl (cbz or Z), melting point (mp), carbonyldiimidazole (CDI), MeSO₂— (mesyl or Ms), 1,4-diazabicyclo[2.2.2]octane(DABCO), mass spectrum (ms) diethylaminosulfur trifluoride (DAST),methyl t-butyl ether (MTBE), dibenzylideneacetone (Dba),N-carboxyanhydride (NCA), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),N-bromosuccinimide (NBS), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N-methylpyrrolidone (NMP), 1,2-dichloroethane (DCE), pyridiniumchlorochromate (PCC), N,N′-dicyclohexylcarbodiimide (DCC), pyridiniumdichromate (PDC), dichloromethane (DCM), propyl (Pr), diethylazodicarboxylate (DEAD), phenyl (Ph), di-iso-propylazodicarboxylate,DIAD, pounds per square inch (psi), diethyl iso-propylamine (DEIPA),pyridine (pyr), di-iso-butylaluminumhydride, DIBAL-H, room temperature,rt or RT, N,N-dimethyl acetamide (DMA), tert-butyldimethylsilyl ort-BuMe₂Si, (TBDMS), 4-N,N-dimethylaminopyridine (DMAP), triethylamine(Et₃N or TEA), N,N-dimethylformamide (DMF), triflate or CF₃SO₂— (Tf),dimethyl sulfoxide (DMSO), trifluoroacetic acid (TFA),1,1′-bis-(diphenylphosphino)ethane (dppe),2,2,6,6-tetramethylheptane-2,6-dione (TMHD),1,1′-bis-(diphenylphosphino)ferrocene (dppf), thin layer chromatography(TLC), ethyl acetate (EtOAc), tetrahydrofuran (THF), diethyl ether(Et₂O), trimethylsilyl or Me₃Si (TMS), ethyl (Et), p-toluenesulfonicacid monohydrate (TsOH or pTsOH), lithium hexamethyl disilazane(LiHMDS), 4-Me-C₆H₄SO₂— or tosyl (Ts), iso-propyl (i-Pr),N-urethane-N-carboxyanhydride (UNCA), ethanol (EtOH). Conventionalnomenclature including the prefixes normal (n), iso (i-), secondary(sec-), tertiary (tert-) and neo have their customary meaning when usedwith an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature inOrganic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).

EMBODIMENTS OF THE INVENTION

The present invention affords a process for the preparation of6-(2-fluoro-3-(hetero)aryloxy-benzyl)-4-alkyl-2H-pyridazin-3-onecompounds (8: R^(4c)=alkyl) and6-(2-fluoro-3-(hetero)aryloxy-benzyl)-2H-pyridazin-3-one compounds (8R^(4c)=hydrogen) compounds, wherein R¹ and R² are as defined in claim 1,and said compounds are chemical intermediates useful for the preparationof said pyridazinones. The process exploits the lability of fluorineatoms in trifluoronitrobenzene and results in the regiospecificdisplacement of two of the three fluorine atoms resulting by the phenoxymoiety and the alkylpyridazinone moiety while retaining a fluorine atomand a nitro group as in 8 (X═NO₂). The nitro group can be furtherreduced to an amine which is further utilized to introduce halogen,alkyl or other substituents into the 4-position. The conversion of anaromatic amine substituent into a variety of other functional groups iswell known, e.g., Cl, Br or F, and the preparation of other pyridazinonecompounds with other substituents at the 4-position is within the scopeof the present invention. A halogen, particularly a bromo or chlorosubstituent can be converted into the corresponding 4-alkyl substitutionby a dialkylzinc in the presence of a palladium catalyst.

Fluoronitroaromatic compounds are known to be unusually sensitive tonucleophilic attack by soft nucleophiles. Fluorine substituents aregenerally significantly more labile than other halogen substituents.While hard nucleophiles like water and hydroxide fail to displacefluoride, soft nucleophiles like phenols, imidazoles, amines, thiols andsome amides facilely displace fluorine at room temperature (D. Boger etal., Biorg. Med. Chem. Lett. 2000 10: 1471-75; F. Terrier NucleophilicAromatic Displacement: The Influence of the Nitro Group VCH Publishers,New York, N.Y. 1991).

The reaction of sodium methoxide with 2,3,4-trifluoronitrobenzene inmethanol has been reported to afford an inseparable mixture of thecorresponding 2- and 4-monomethoxy and 2,4-dimethoxy derivatives (P. M.O'Neill et al., J. Med. Chem. 1994 37:1362-70). Displacement of theortho-fluorine of 2,4-difluoronitrobenzene by amine nucleophiles alsohas been reported. (W. C. Lumma, Jr. et al., J. Med. Chem. 198124:93-101).

The reaction of 2,3,4-trifluoronitrobenzene (Aldrich catalog No. 33,836-2) with 3-chloro-5-cyanophenol resulted in regiospecificdisplacement of the 2-fluoro moiety to afford 9. One skilled in the artwill immediately appreciate that although the process is exemplifiedwith 3-chloro-5-cyanophenol, a large number of substituted phenols orhydroxyl substituted heteroaromatic compounds are readily available andcould be used to afford many other anti-HIV-compounds.

The displacement reaction can be run in a variety of organic solventsincluding, but not limited to, ethers (e.g. diethyl ether, THF, DME anddioxane) and alcohols (e.g., iso-propanol and sec-butanol). Solventscapable of directly reacting with the fluoronitrobenzene are clearlyprecluded as are solvents which may result in the loss of regiochemicalcontrol. Thus secondary and tertiary alcohols are acceptable solventsbut primary alcohols can displace fluoride. The skilled chemist would becapable of identifying acceptable solvents with minimal experimentation.The phenol is treated with base to afford the phenolate salt. Any alkalimetal salt can be employed in the present process but the reaction isconveniently carried out with the lithium, sodium or potassium salts.Sodium phenolates are readily available by treating the phenol withsodium tert-butoxide or sodium tert-amylate in tert-butanol or tert-amylalcohol respectively. The sodium alcoholate can be prepared by treatingthe alcohol with sodium metal or sodium hydride. Potassium phenolatescan be prepared analogously. Alternatively the phenol can be combinedwith the sodium alcoholate in THF to afford the salt. The reaction canbe run from about −30° C. to about 40° C. without significant loss ofthe regioselectivity. Typically the reactants are combined at lowtemperature and allowed to warm to RT after an initial mixing. Underthese conditions the aromatic nucleophilic displacement proceeds withhigh regioselectivity at the 2-position of the substrate

Introduction of the carbon substituent at the 4-position of the benzenering was achieved by a second subsequent regioselective aromaticnucleophilic displacement with a carbon nucleophile. Suitable carbonnucleophiles are obtained by deprotonation of a carboxylic acidderivative or a malonic acid diester. Deprotonation of a carboxylic acidester or a nitrile is accomplished with lithium or sodium amide basessuch as lithium diisopropylamide, lithium hexamethyldisilazane, lithiumdiethylamide. Deprotonation also can be effected with sodium orpotassium alkoxides or with potassium or sodium hydrides. Thedeprotonation is generally accomplished in ethereal solvents or polaraprotic solvents at temperatures from about −70° C. to about 0° C.Direct introduction of the pyridazinone is achieved by reacting 9 with(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl ester(10). Advantageously, condensation of 9 and 10 regiospecifically affordsthe 4-methyl compound and tedious separation of the 4-alkyl and5-alkylpyridazinone isomers is avoided.

The skilled artisan will comprehend that while use of (hetero)arylaceticacid compounds, such as 10, is sometimes advantageous, the introductionof the (hetero)aryl moiety can also be achieved by a multistep processemploying malonic acid diesters. Alkylation of dialkyl malonates, andvariations such as mixed diesters, are a fundamental process in organicsynthesis and a multitude of variations applicable to the presentprocess have been described (H. O. House, Modern Synthetic Reactions, 2ed., W. A. Benjamin, 1972, New York N.Y., pp. 492-570 and 586-595; W.Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd) ed.,Cambridge University Press, Cambridge, UK, 1986, pp. 1-26). For example,

ethyl tert-butyl malonate (12), reacts efficiently with 9 to afford 13.The resulting 3-(phenoxyphenyl)-substituted malonate 13 can be furthersubstituted by a second deprotonation and alkylation or converted to acorresponding phenylacetate (14: R═H) by hydrolysis and decarboxylation.The resulting phenylacetate can, for example, be condensed with3,6-dichloropyrazine to afford unsubstituted 6-chloropyridazines (15a)which can be converted to the corresponding pyridazinone (15b) bysequential acid hydrolysis and decarboxylation. Considerable flexibilityis possible in the sequence of steps and all variations are consideredto be within the scope of the invention.

Thus, in one embodiment of the present invention there is provided aprocess for the preparation

of a compound according to formula I wherein R¹ is A or B; R² is an arylradical or a heteroaryl radical wherein said heteroaryl is selected fromthe group consisting of pyridinyl, pyridine N-oxide, indole, indoleN-oxide, pyrimidinyl, pyrazinyl, quinoline, quinoline N-oxide andpyrrolyl; and, said aryl radical and said heteroaryl radical areoptionally substituted with zero to three substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ sulfonyl, C₁₋₆ haloalkoxy, C₁₋₆ haloalkylthio,hydroxy, halogen, amino, C₁₋₁₆ alkylamino, C₁₋₁₆ dialkylamino,aminoacyl, acyl, C₁₋₁₆ alkoxycarbonyl, carbamoyl, C₁₋₆ N-alkylcarbamoyl,C₁₋₆ N,N-dialkylcarbamoyl, nitro and cyano; R^(4a) is hydrogen C₁₋₆alkyl, tert-butyl or benzyl; R^(4b) is hydrogen or —CO₂R^(4a) and,R^(4c) is hydrogen or C₁₋₆ alkyl comprising the steps of: (i) contactingan alkali metal (hetero)aryloxide II with 2,3,4-trifluoronitrobenzene ina first solvent at temperatures from about −30° C. up to about 40° C. toafford a 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III;

(ii) further contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzenecompound III with alkali metal salt of an acetic acid ester IV whereinR⁵ is CO₂R^(5a) or C and R^(5a) is independently in each occurencestraight or branched C₁₋₆ alkyl, in second solvent at a temperature ofat least about −78° C. up to about 40° C. to afford a2-fluoro-3-phenoxyphenylacetic ester V.

Suitable first solvents include, but are not limited to etherealsolvents and secondary and tertiary alcohols. The choice of a suitablebase and second solvent will be influenced by the reactants. The secondsolvent is typically an polar aprotic solvent or an ethereal solventwhen strong bases, e.g. alkali metal amides. Aprotic ether solvents mayalso be used when sodium or potassium alkoxides are used as the base.Alkali metal hydrides are typically used in polar aprotic solvents. Theskilled chemist will readily identify suitable combinations of bases andsolvents

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula V whereinR² is 3,5-bis-tert-butylcarbamoyl-phenyl or 3-chloro-5-cyanophenyl whichprocess comprises (i) contacting an sodium3,5-bis-tert-butylcarbamoyl-phenolate or sodium3-chloro-5-cyano-phenolate with 2,3,4-trifluoronitrobenzene in a firstsolvent at temperatures from about −30° C. up to about 40° C. to afforda 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene or3,4-difluoro-2-(3-chloro-5-cyano-phenoxy)nitrobenzene which is furtherreacted with IV as described below.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula IIIwherein R² is 3,5-dicyano-phenyl which process further comprises (i)contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with2,3,4-trifluoronitrobenzene in an appropriate solvent at temperaturesfrom about −30° C. up to about 40° C. to afford a3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and(ii) contacting3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene withphosphorus oxychloride or a similar dehydrating agent to afford3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene 111(R²=3,5-dicyanophenyl). The ether can be convert to IV(R²=3,5-dicyanophenyl) as described below.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula VI whichprocess comprises the steps of (i) contacting an alkali metal(hetero)aryloxide II with 2,3,4-trifluoronitrobenzene in a first solventat temperatures from about −30° C. up to about 40° C. to afford a3,4-difluoro-2-(hetero) aryloxynitrobenzene compound III; (ii)contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound IIIwith alkali metal salt of an acetic acid ester IV wherein R⁵ isCO₂R^(5a) or C and R^(5a) is independently in each occurence straight orbranched C₁₋₆ alkyl, in a second solvent with a base at a temperature ofat least about −78° C. up to about 40° C. to afford a2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono- ordi-ester and contacting the resulting mono- or di-acid with acid toafford VI wherein R⁵ is CO₂R^(4a) or C and R^(4a) or R^(4c) is hydrogenor C₁₋₆ alkyl; and, R¹, R² and R^(4b) are as defined in claim 1.

Replacement of the nitro group with other substituents can be achievedby a two-step process comprising reduction of the nitro compound VI tothe corresponding amine VII. Reduction of a nitro group to an amine iswell known and can be accomplished with inorganic reducing agents, e.g.iron, zinc and tin salts in acidic solvents, or by catalytichydrogenation. Other conditions which can be employed in the reductionof aromatic nitro groups include AlH₃—AlCl₃, hydrazine, TiCl₃,Al—NiCl₂-THF, formic acid and sulfides such as NaHS, (NH₄)₂S orpolysulfides. Aromatic nitro compounds have been reduced to amines byNaBH₄ in the presence of transition metal catalysts such as NiCl₂ orCoCl₂. (J. March, Advanced Organic Chemistry J. Wiley & Sons, New York,1992 p 1216-1217).

Aryl chlorides and bromides can be prepared form the correspondingdiazonium salt by treating the diazonium salt with cuprous chloride orcuprous bromide (the Sandmeyer Reaction). Aryl diazonium salts areprepared by treating the amine dissolved in dilute mineral acids andcooled to about 0° to about 10° C. with aqueous sodium nitrite. Lessreactive weakly basic amines require concentrated acids, e.g. con H₂SO₄,or mixtures of con H₂SO₄ and glacial acetic acid or phosphoric acid.Fluoroboric acid has also proven useful. An alternate process can becarried out in an organic solvent, e.g., glacial HOAc, MeOH, EtOH,HCONH₂, DMF, acetone and others, using nitrite esters, e.g., butyl- orpentyl-nitrite. Other nitrosating agents which can be employed innon-protic solvents include nitrosyl chloride, nitrosyltetrafluoroborate and the like (K. Schank Synthetic Applications ofDiazonium Ions in The Chemistry of the Diazonium and Diazo Group, S.Patai (ed), Part 2, 1978 John Wiley & Sons, New York, N.Y., pp.647-648.). Aryl chlorides and bromides are formed efficiently bytreating the aryl diazonium salt with CuCl or CuBr. A variant of theSandmeyer procedure uses metallic copper in the presence of hydrochloricor hydrobromic acid (the Gatterman reaction). One-step alternatives twothe two step diazotization/Sandmeyer sequence include treating the aminewith t-butyl nitrite and cuprous chloride or bromide at elevatedtemperatures (M. P. Doyle et al. J. Org. Chem. 1977 42:2426) or witht-butyl thionitrate and the cuprous halides at room temperature (S. Oaeet al. Bull. Chem. Soc. Japan 1980 53:1065). Aryl fluorides areaccessible from daizonium compounds via the Schiemann Reaction (H.Suschitzky Adv. Fluorine Chem. 1965 4:1-30). The Schiemann reaction iscarried out by treating a diazonium salt, formed by standard protocols,with NaBF₄, HBF₄ or NH₄BF₄ to form a diazonium tetrafluoroborate saltwhich can be isolated and thermally converted to the desired arylfluoride while releasing nitrogen and BF₃. Other fluoride salts such asPF₆ ⁻, SbF₆ ⁻ and AsF₆ ⁻ also can be used. Aryl chlorides and bromidesare also accessible through the corresponding tetrachloroborate andtetrabromoborate salts (G. Olah and W. S. Tolgyesi J. Org. Chem. 196126:2053). Aryl iodides are prepared by treating the diazonium salt withiodine.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula VII whichprocess comprises the steps of (i) contacting an alkali metal(hetero)aryloxide II with 2,3,4-trifluoronitrobenzene in a first solventat temperatures from about −30° C. up to about 40° C. to afford a3,4-difluoro-2-(hetero) aryloxynitrobenzene compound III; (ii)contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound IIIwith alkali metal salt of an acetic acid ester IV wherein R⁵ isCO₂R^(5a) or C and R^(5a) is independently in each incidence straight orbranched C₁₋₆ alkyl, in a second solvent with a base at a temperature ofat least about −70° C. up to about 40° C. to afford a2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono- ordi- and contacting the resulting mono- or di-acid with acid to afford VIand (iv) contacting VI with a reducing agent to afford amine VII,wherein R⁵ is CO₂R^(4a) or C and R^(4a) or R^(4c) is hydrogen or C₁₋₆alkyl; and, R¹, R² and R^(4b) are as in claim 1.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula VIII(X=Cl or Br) which process comprises the steps of (i) contacting analkali metal (hetero)aryloxide II with 2,3,4-trifluoronitrobenzene in afirst solvent at temperatures from about −30° C. up to about 40° C. toafford a 3,4-difluoro-2-(hetero) aryloxynitrobenzene compound III; (ii)contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound IIIwith alkali metal salt of an acetic acid ester IV wherein R⁵ isCO₂R^(5a) or C and R^(5a) is independently in each incidence straight or

branched C₁₋₆ alkyl, in an aprotic solvent with a base at a temperatureof at least about −70° C. up to about 40° C. to afford a2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono- ordi-ester and contacting the resulting mono- or di-acid with acid toafford VI; (iv) contacting VI with a reducing agent to afford amine VII;and (v) contacting the amine VII with a diazotizing agent andsubsequently contacting the resulting diazonium salt with a cuproushalide to afford VIII, wherein X is chloro or bromo, R⁵ is CO₂R^(4a) orC and R^(4a) or R^(4c) is hydrogen or C₁₋₆ alkyl and R¹, R² and R^(4b)are as defined in claim 1.

a compound according to formula VIII (X═F) which process comprises thesteps of (i) contacting an alkali metal (hetero)aryloxide I with2,3,4-trifluoronitrobenzene in a first solvent at temperatures fromabout −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III; (ii) contacting said3,4-difluoro-2-(hetero)aryloxynitrobenzene compound III with alkalimetal salt of an acetic acid ester IV wherein R⁵ is CO₂R^(5a) or C andR^(5a) is independently in each occurence straight or branched C₁₋₆alkyl, in an aprotic solvent with a base at a temperature of at leastabout −70° C. up to about 40° C. to afford a2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono- ordi-ester and contacting the resulting mono- or di-acid with acid toafford VI; (iv) contacting VI with a reducing agent to afford amine VII;and (v) contacting the amine VII with a diazotizing agent in thepresence of a tetrafluoroborate salt or tetrafluoroboric acid andheating said diazonium tetrafluoroborate to afford VIII where X isfluorine, R⁵ is CO₂R^(4a) or C and R^(4a) or R^(4c) is hydrogen or C₁₋₆alkyl and R¹, R² and R^(4b) are as defined in claim 1.

In another embodiment of the present invention there is provided aprocess for the preparation of a compound according to formula VIII(X=alkyl) which process comprises the steps of (i) contacting an alkalimetal (hetero)aryloxide II with 2,3,4-trifluoronitrobenzene in a firstsolvent at temperatures from about −30° C. up to about 40° C. to afforda 3,4-difluoro-2-(hetero) aryloxynitrobenzene compound III; (ii)contacting said 3,4-difluoro-2-(hetero)aryloxynitrobenzene compound IIIwith alkali metal salt of an acetic acid ester IV wherein R⁵ isCO₂R^(5a) or C and R^(5a) is independently in each occurence straight orbranched C₁₋₆ alkyl, in an aprotic solvent with a base at a temperatureof at least about −70° C. up to about 40° C. to afford a2-fluoro-3-phenoxyphenylacetic ester V; (iii) hydrolyzing the mono- ordi-ester and contacting the resulting mono- or di-acid with acid toafford VI; (iv) contacting VI with a reducing agent to afford amine VII;and (v) contacting the amine VII with a diazotizing agent and contactingthe diazonium salt with CuBr to afford VIII wherein X is a Br, and (vi)contacting the aryl bromide with a dialkyl zinc Pd(dppf)Cl₂ and DIBAL toafford VIII (X=alkyl), wherein R⁵ is CO₂R^(4a) or C and R^(4a) or R^(4c)is hydrogen or C₁₋₆ alkyl and R¹, R² and R^(4b) are as defined in claim1.

In another embodiment of the present invention there is provided acompound according to formula III wherein R² is as defined in claim 1.

In another embodiment of the present invention there is provided acompound according to formula V wherein R², R^(4a), R^(4c) and R⁵ are asdefined in claim 1.

The pyridazinone 10 was obtained utilizing the Wittig reaction. (see J.W. Schulenberger and S. Archer, Organic Reactions, Wiley & Sons, NewYork 1965 vol. 14, chapter 1, pp. 1-51; J. March, Advanced OrganicChemistry, 4^(th) ed., John Wiley & Sons, New York, 1992, pp. 956-963).The phosphorane 16 was condensed with citraconic anhydride 17 whichproduced an isomeric mixture alkylidene lactones from which the majorisomer 18 could be isolated by crystallization (Massy-Westropp, R. A.and Price, M. F., Aust. J. Chem. 1980, 33, 333-341). Treating 18 withhydrazine afforded (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-aceticacid tert-butyl ester (10). The present invention thus provides aconvergent synthesis in which separation of the regioisomers is possibleon an easily accessible intermediate early in the synthetic sequence.

The following examples (infra) are given to enable those skilled in theart to more clearly understand and to practice the present invention.They should not be considered as limiting the scope of the invention,but merely as being illustrative and representative thereof.

Example 15-[6-Chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-isophthalonitrile

A 22 L round-bottom flask was charged with3,5-bis-tert-butylcarbamoyl-phenol (20, 360 g, 1.23 mol) and THF (12.5L). The resulting slurry was cooled to 0° C. and potassium tert-butoxide(1.35 L, 1.0 M in THF, 1.35 mol) was added dropwise over approximately30 min. After the addition was complete, the reaction mixture was cooledto between −30 and −35° C. and 2,3,4-trifluoronitrobenzene (239, 1.35mol) was added dropwise over approximately 5 min. The reaction mixturewas stirred at approximately −30° C. for 1 h whereupon the cooling bathwas removed. The reaction mixture was then stirred for 20 h with warmingto ambient temperature. A mixture of water (2.0 L) and brine (1.0 L) wasadded, and the reaction mixture was stirred vigorously in a 20 Lextractor ball. Following removal of the aqueous phase, the organiclayer was washed with additional brine (1.5 L), and the resulting THFsolution was transferred to a 22 L round bottom flask for distillation.The extractor ball was rinsed with THF (500 mL). After approximately 10L of THF had been removed by distillation, addition of isopropyl alcohol(11 L) was initiated and the distillation was continued untilapproximately 23 L of distillate had been collected. When the residualvolume was 5 L and the pot temperature was 82° C., water (2.0 L) wasadded dropwise. Heating was then discontinued, and the reaction mixturewas stirred overnight with cooling to room temperature. The resultingsolid was filtered through a 3 L course-frit sintered glass filterfunnel. The filter cake was washed with IPA/H₂O (1:1, 2×600 mL) anddried in a vacuum oven (70° C., 25 Torr) to affordN,N′-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide (21;488 g, 88% theory).

A 5 L round bottom flask was charged withN,N′-di-tert-butyl-5-(2,3-difluoro-6-nitro-phenoxy)-isophthalamide (21;564 g) and 1.3 L of phosphorus oxychloride. The mixture was heated tobetween 90° C. and 100° C. for 2 h after which approximately 1/2 of thePOCl₃ was removed by distillation. Toluene was added (1 L) andadditional liquid was distilled. Cooling the mixture overnight andfiltering the solid gave crude product. Additional material was obtainedby further concentration, treatment with water (2 L) and filtration ofthe resulting material. The combined solids were stirred in MeOH (0.7 L)for between 1 and 3 h, filtered and dried in a vacuum oven between 50°C. and 80° C. at 25 Torr with a nitrogen bleed to afford 339 g of 22(90% theory).

A 5 L three-neck round bottom flask was charged with(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-3-yl)-acetic acid tert-butylester (10; 223 g, 0.996 mol) and THF (700 mL). The resulting solutionwas cooled to 0° C. and potassium tert-butoxide (1.2 L, 1.66 M in THF,1.99 mol) was added dropwise over approximately 30 min. After coolingthe reaction mixture to −55° C., a solution of5-(2,3-difluoro-6-nitro-phenoxy)-isophthalonitrile (22; 150 g; 0.498mol) in THF (1.0 L) was added dropwise over approximately 1 h. Followinga THF rinse (500 mL), the cooling bath was removed, and the reactionmixture was stirred for 19 h with warming to ambient temperature. Thereaction mixture was then quenched by the addition of 1N HCl (1.75 L).Following removal of the aqueous layer (2 L, pH of 3-4) the organicphase was washed with water (1.0 L) and brine (750 mL). The resultingTHF solution was filtered through CELITE® and the filter aid washed withTHF (500 mL). The solution was then concentrated in vacuo to afford adark oil which was dissolved in NMP (850 mL) and warmed to approximately50° C. Water (425 mL) was added dropwise. The cloudy solution wasstirred slowly, seeded with a crystal and cooled to 0° C. After stirringat 0° C. for 30 min, the product was filtered. The filter cake was thenwashed with MeOH (100 mL, 200 mL) and dried in a vacuum oven (50° C., 25Torr) to afford[3-(3,5-dicyano-phenoxy)-2-fluoro-4-nitro-phenyl]-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-aceticacid tert-butyl ester (23; 157 g, 62% theory).

A slurry of 23 (771.1 g), methanesulfonic acid (100 mL) and acetonitrile(1.5 L) was heated to 70° C. under a N₂ atmosphere for 2 h. The solutionbecame homogenous at approximately 52° C. and a solid precipitatereformed after 30 min at 70° C. The reaction mixture was diluted withwater (3084 mL) and IPA (3084 μL) and the resulting mixture was aged at63° C. for 1 h. The heating was stopped and the resulting solutionallowed to slowly cool to RT. The solid product was recovered byfiltration and the resulting filter cake was thrice washed with H₂O:MeOH(1:1, 500 mL) and dried overnight in a vacuum oven at 80° C. whichafforded 24 (603.5 g, 97.6% theory).

A suspension of5-[2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-6-nitro-phenoxy]-isophthalonitrile(24; 200 g, 0.494 mol) in THF (3.2 L) was warmed to 66° C. to dissolvethe solid and the solution was cooled to RT. To resulting solution wasadded VO(acac)₂ (6.542 g, 24.7 mmol) and 5% palladium (sulfided) oncarbon (JM Catalyst # 11; 10.0 g) and the resulting suspension wasstirred overnight at RT under a hydrogen atmosphere. The resultingsuspension was filtered and the solvent was removed in a rotaryevaporator (approximately 2.7 L), a solid precipitate formed and IPA(2.0 L) was added. An additional 600 mL of solvent was removed byevaporation after which the suspension was aged at 40° C. for 5 h andthen cooled to RT. The solid was filtered and washed thrice with H₂O:IPA(1:1 v/v, approximately 700 mL). The filtrate and washes were combinedand concentrated to afford an additional 23.3 g of product. There wasobtained 375.4 g (98% theory) of5-[6-amino-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-isophthalonitrile(25).

A suspension of 25 (156 g, 0.416 mol) and THF (3.7 L) was heated toreflux to dissolve the amine and approximately 2.3 L of THF wasdistilled from the solution. A solution of BF₃ etherate (78.3 mL, 88.48g, 0.623 mol) and 200 mL of THF was cooled to −15° C. The amine solutionwas pumped into the cooled solution approximately 10 min. The reactionmixture was then maintained at −15° C. for 15 minutes. A solution oftert-butyl nitrite (51.43 g, 0.499 mol) and THF (50 mL) was added over a5 min period. The cooling bath was removed and the mixture allowed towarm. After 2.5 h the reaction was quenched by the addition of 2.25 Lhexane and the resulting solid was stirred and finally filtered. Thesolid was washed with hexane (4×500 mL) and the resulting solid wasdried in a vacuum oven overnight at 30° C. to afford 198 g of thediazonium tetrafluoroborate salt.

CuCl was suspended in MeCN (600 mL) and heated to 65° C. A suspension ofthe crude diazonium tetrafluoroborate in MeCN (900 mL) was pumped intothe cuprous chloride solution over a 10 min period. The pump was washedwith MeCN (350 mL). After 1 h at 65° C. the reaction mixture was cooledto about 40° C. and 3M HCl (2.0 L) was added, after which cyclohexane(2.0 L) was added and stirred for 15 min. The resulting precipitate wasfiltered and washed with water (250 mL) and EtOH (2×400 mL) to afford alight yellow solid which was dried in a vacuum oven at 55° C. to afford26 (131.6 g, 84.9% theory). An additional 16 g of product was obtainedby extracting the aqueous phase with twice with DCM (2.0 L), evaporatingthe organic phase and chromatographing the resulting oil on silica gel.

3-Chloro-5-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-benzonitrileand3-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-5-fluoro-benzonitrilewas prepared by an analogous procedure except 3-chloro-5-cyanophenol and3-cyano-5-fluorophenol respectively were substituted for 20 and thePOCl₃ dehydration (step 2) was omitted.

Example 2 (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acidtert-butyl ester (10)

To a cooled (12° C.) solution of the phosphorane (16; 3.008 Kg; 7.99mol) in THF (12 L) was added citraconic anhydride (1.35 Kg; 12.04 mol)over a 4 h period during which the temperature rose to 35 C. Followingthe addition, approximately 10 L of THF was removed by distillation andreplaced with 4 L of methanol. Addition liquid was removed bydistillation and replaced by methanol. A total of 14.6 L was distilledand 7 L of methanol added. To the mixture was added 1 L of water and 6 Lof cyclohexane. The cyclohexane layer was separated, and the lower(methanol-water) layer was repeatedly extracted with cyclohexane (atotal of 12 extractions each with approximately 6 L of cyclohexane). Thecyclohexane fractions were combined and concentrated on a rotaryevaporator. After solvent removal, methanol (1 L) was added and themixture further concentrated on a rotary evaporator. The resulting oilwas taken up in methanol (2 L) and cooled to −12° C. for 3 h. Afterfiltration, the solid cake was washed with MeOH (400 mL cooled to 0° C.)and the solid was dried in a vacuum desiccator to afford(4-ethyl-S-oxo-5H-furan-2-ylidene)-acetic acid tert-butyl ester (18, 950g; 56.6% yield).

To a solution of lactone 18 (2.68 Kg; 12.77 mol) in 7.5 L of NMP cooledto below 0° C. was added 420 mL of anhydrous hydrazine (equivalentquantities of hydrazine hydrate also can be used) while maintaining theinternal temperature at less than 20° C. After the addition wascompleted the reaction mixture was heated to 110-145° C. for one to fiveh. The reaction mixture was cooled and diluted with H₂O (11 L) whichresulted in the formation of crystalline pyridazinone 10 which wasfiltered and washed with water (2×2 L) and dried to afford 2.23 Kg(77.9%) of product.

Example 36-[4-Chloro-2-fluoro-3-(1H-indol-7-yloxy)-benzyl]-4-methyl-2H-pyridazin-3-one(31)

Solid sodium tert-butoxide was added to a ice cold solution of7-hydroxyindole (1.23 g, 9.24 mmol; Synthetic Communications 200333:507) in anhydrous THF (145 mL) under a nitrogen atmosphere. Themixture was stirred for 10 min, and 2,3,4-trifluoronitrobenzene (1.06mL, 9.24 mmol) was added dropwise. The brown solution was stirred for 2h, and then added to a saturated aqueous solution of NH₄Cl (150 mL). Theaqueous layer was extracted with EtOAc (3×100 mL), and the combinedorganic fractions were washed with H₂O (100 mL), brine (75 mL), anddried over anhydrous MgSO₄. The solvents were evaporated, and theremaining oil was purified by flash chromatography on silica gel (0% to30% EtOAc/hexanes) to afford 2.26 g (84%) of 27.

Phenyl sulfonyl chloride (1.05 mL, 8.18 mmol), powdered NaOH (4 g), andBu₄NHSO₄ (400 mg) were added sequentially to a solution of 27 (2.26 g,7.79 mmol) in anhydrous CH₂Cl₂ (25 mL). The mixture was stirred for 3 h,and then filtered through CELITE®. The filtrate was washed with H₂O (25mL), and dried over anhydrous MgSO₄. The solvents were evaporated, andthe remaining material was recrystallized from EtOAc. The impurefiltrate was purified by column chromatography on silica gel (25% to 40%EtOAc/hexanes), and combined with the crystallized material to afford2.08 g (62%) of 28.

A solution of sodium hexamethyldisilazane (15.5 mL of a 1 M solution inTHF, 15.5 mmol) was added slowly to a solution of 28 (2.08 g, 4.83 mmol)and 10 (1.14 g, 5.07 mmol) in anhydrous THF (25 mL) under nitrogen at 0°C. The reaction mixture was stirred for 3 h, and then added to asaturated aqueous solution of NH₄Cl (200 mL). The aqueous mixture wasextracted with EtOAc (3×70 mL). The combined organic fractions were thenwashed with brine (50 mL), and dried over anhydrous MgSO₄. Evaporationof the solvents afforded a red oil which was dissolved in acetic acid(100 mL) and heated to reflux for 5 h. The solvent was removed, and theremaining material was dissolved in EtOAc (100 μL). The organic layerwas washed with H₂O (40 mL), brine (25 mL), and dried over anhydrousMgSO₄. The solvents were evaporated and the crude product purified byflash chromatography on silica gel (20% to 100% EtOAc/hexanes) to afford29 (1.79 g, 69%) as a solid that was only slightly soluble in EtOAc.

A mixture of pyridazinone 29 (1.79 g, 3.36 mmol), Fe powder (845 mg,15.12 mmol), and NH₄Cl (809 mg, 15.12 mmol) in EtOH (60 mL) and H₂O (15mL) was heated to reflux for 3 h. The reaction mixture was cooled to RTand filtered through CELITE®. The filter cake was washed with EtOAc (150mL), and the combined organic fractions were washed with brine (75 mL),and dried over anhydrous MgSO₄. The solvents were evaporated to providean oil. The oil was dissolved in CH₂Cl₂ (100 mL), and the organic layerwas washed with brine (50 mL), and dried over anhydrous MgSO₄.Evaporation of the solvent provided 30 (1.50 g; 88% theory).

The aniline 30 (700 mg, 1.39 mmol) and CuCl₂ (381 mg, 2.77 mmol) weresuspended in anhydrous CH₃CN (14 mL) under a nitrogen atmosphere.tert-Butylnitrite (0.33 mL, 2.77 mmol) was added dropwise, and thereaction mixture was warmed to 60° C. for 1 h. The solution was cooledto RT, and a 5% aqueous HCl solution (20 mL) was added. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×30 mL). Thecombined organic fractions were washed with brine (30 mL) and dried overanhydrous MgSO₄. The solvents were evaporated, and the remaining solidwas purified by flash chromatography over silica gel (20% to 100%EtOAc/Hexanes) to provide 500 mg of a solid. The solid was dissolved inanhydrous THF (10 mL) under nitrogen, and TBAF was added dropwise (5.73mL of a 1.0 M solution, 5.73 mmol). The solution was heated to refluxfor 1 h and then cooled to RT. The mixture was quenched with saturatedaqueous NaHCO₃, and the aqueous solution was extracted with CH₂Cl₂ (3×30mL). The combined organic fractions were washed with H₂O (30 mL), brine(30 mL), and dried over anhydrous MgSO₄. The solvents were evaporated,and the remaining solid was purified by repeated flash chromatography onsilica gel (1% to 3% MeOH/CH₂Cl₂) to afford 31 (135 mg; 25% theory).

Example 46-[3-(5-bromo-1-oxy-pyridin-3-yloxy)-4-chloro-2-fluoro-benzyl]-4-methyl-2H-pyridazin-3-one(41)

A solution of 3,5-dibromopyridine (32, 20 g, 84.4 mmol) in DMF (200 mL)was stirred at RT under nitrogen atmosphere and 21.3 mL of sodiummethoxide (25% by wt. in methanol, 92.8 mmol) was added slowly. Thereaction mixture was stirred overnight at 70° C. under N₂. The reactionwas cooled to RT and quenched with water (200 mL) and extracted withEt₂O (2×200 mL). The combined organic extracts was washed with brine,dried (MgSO₄) and concentrated in vacuo. The crude3-bromo-5-methoxypyridine (33, 14.8 g, 93% theory) afforded a colorlessoil after flash chromatography on silica gel (EtOAc:hexane 1:10).

A solution of 3-bromo-5-methoxy-pyridine (33 18.8 g, 0.1 mol), HBr (80mL, 48%) and glacial HOAc (60 mL) was stirred overnight at 120° C.Hydrobromic acid (60 mL, 48%) was added slowly to replace evaporatedsolvents and stirred at 120° C. for overnight. The reaction mixture wascooled to RT and then poured into the ice. The pH was adjusted to about6 by adding 6N NaOH and then extracted with EtOAc (2×200 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was stirred in CH₂Cl₂ (150 mL) and the resulting precipitate wasfiltered. The product was washed with CH₂Cl₂ to afford3-bromo-5-hydroxypyridine (34; 15.2 g, 87.4% theory) as a white solid.

A solution of 3-bromo-5-hydroxypyridine (34, 7.4 g, 42.5 mmol) inanhydrous THF (40 mL) was stirred at 0° C. under Ar atmosphere andpotassium tert-butoxide (46.8 mL, 1 M solution in THF) was added slowly.After 1 h at 0° C., 2,3,4-trifluoronitrobenzene (7.91 g, 44.6 mmol) in15 mL of THF was added very slowly. The reaction mixture was stirred atRT for 2 h, quenched with water (80 mL) and extracted with EtOAc (2×80mL). The combined organic extracts were dried (MgSO₄) and concentratedin vacuo. The crude product was purified by flash chromatography onsilica gel (EtOAc:hexane 1:15) to afford 35 (11 g, 78%) as a lightorange oil.

A solution of (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acidtert-butyl ester (10, 7.1 g, 31.7 mmol) and 35 (1 g, 33.3 mmol) inanhydrous THF (30 mL) was stirred at −78° C. under an Ar atmosphere and112 mL of LiHMDS (1.0M solution in THF) was added very slowly. Thereaction mixture was stirred in the cold bath (dry-ice/IPA) for 3 h thenin an ice bath for 2 h. The reaction was quenched with a solution ofNaHSO₄.H₂O (5% by wt) and extracted with EtOAc (2×100 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo. Theproduct was isolated by a flash chromatography on silica gel(EtOAc:hexane 1:2 to 2:1) to afford 36 as a yellow solid (10.2 g, 60%yield).

A solution of 36 (10.2 g, 19.1 mmol) in HOAc (120 mL) under a nitrogenatmosphere was heated to reflux overnight. It was cooled to RT and theHOAc was evaporated in vacuo. A saturated NaHCO₃ solution (70 mL) wasadded and the aqueous mixture extracted with EtOAc (2×80 mL). Thecombined organic fractions were dried (MgSO₄) and concentrated in vacuo.The crude product was isolated by a flash chromatography. on silica gel(EtOAc:hexane 1:2 to 2:1) to afford 37 as a light yellow solid (4.6 g,55.3% theory): ms (M+H)⁺=436.

A solution of 37 (1.8 g, 4.4 mmol), di-tert-butyl dicarbonate (1.16 g,5.3 mmol), and 4-dimethylaminopyridine (0.2 g) in anhydrous THF (30 mL)was maintained under an Ar atmosphere and stirred at RT overnight. Thereaction mixture was quenched with water and extracted with EtOAc (2×30mL). The combined organic fractions were dried (MgSO₄) and concentratedin vacuo. The product was isolated by a flash chromatography on silicagel (1:10 to 2:1 EtOAc:hexane) to afford 38 as a white solid compound(0.85 g; 38% theory).

To a solution of 38 (4 g; 9.19 mmol) in absolute EtOH (60 mL) was addedNH₄Cl (0.984 g, 18.40 mmol) dissolved in water (10 mL). The resultingmixture was heated at 60° C. until the reaction was homogeneous. Fe(0)(0.77 g, 13.78 mmol) was then added and the mixture stirred vigorouslyat 60° C. for 6 h. When reduction was complete the hot reaction mixturewas filtered through a pad of CELITE® which subsequently was washed withhot EtOAc. The resulting filtrated was cooled and extracted with EtOAcand the combined extracts washed sequentially with water and brine. TheEtOAc extract was dried (Na₂SO₄), filtered and the volatile solvent wasremoved in vacuo to afford a pale orange oil which was recrystallizedfrom hexanes to yield 39 (1.8 g, 48.3% theory).

Aniline 39 (0.85 g, 1.69 mmol) and CuCl₂ (575 mg, 3.37 mmol) weresuspended in anhydrous CH₃CN (20 mL) under a nitrogen atmosphere.tert-Butyl nitrite (0.348 g, 3.37 mmol) was added dropwise, and thereaction mixture was warmed to 60° C. for 1 h. The solution was cooledto RT, and a 5% aqueous HCl solution (20 mL) was added. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×30 mL). Thecombined organic fractions were washed with brine (30 mL) and dried overanhydrous MgSO₄. The solvents were evaporated, and the remaining solidwas purified by flash chromatography over silica gel (20% to 100%EtOAc/hexanes) to provide 500 mg of a solid. The solid was dissolved inanhydrous DME (10 mL) and TFA (1 mL) was added. The solution was stirredat RT for 1 h. The mixture was quenched with saturated aqueous NaHCO₃,and the aqueous solution was extracted with CH₂Cl₂ (3×30 mL). Thecombined organic fractions were washed with H₂O (30 mL), brine (30 mL),and dried over anhydrous MgSO₄. The solvents were evaporated, and theremaining solid was purified by repeated flash chromatography on silicagel (1% to 3% MeOH/CH₂Cl₂) to afford 40 (290 mg; 49.9% theory; mp184.9-188° C., ms [M+H]⁺=424).

A solution of the pyridine 40 (0.2 g, 0.47 mmol) and MCPBA (0.09 g, 0.52mmol) in anhydrous chloroform (10 mL) was heated at reflux for 6 hours.The reaction mixture was cooled to RT, and diluted with 0.05N NaOH (5mL) and extracted with chloroform (2×10 mL). The combined organicfractions were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by a flash chromatography on silica gel(MeOH:CH₂Cl₂ 0.1 to 1:10) to afford6-[3-(5-bromo-1-oxy-pyridin-3-yloxy)-4-chloro-2-fluoro-benzyl]-4-methyl-2H-pyridazin-3-one(41, 60 mg; 32% theory) as a white solid: mp 197.9-198.9° C., ms(M+H)⁺=440.

Example 5

To a 250 mL round bottom flask charged with 3,5-dichlorobenzonitrile(42; 7.31 g; 34.90 mmol) and maintained under an argon atmosphere wasadded DMF (70 mL). The flask was cooled to 0° C. and powdered sodiummethoxide (1.88 g; 34.90 mmol) was added in two portions 15 min apart.The homogeneous mixture was allowed to warm to room temperature andstirred for 24 h. The solution was cooled to 0° C. and aqueous 10% HCl(20 mL) was added dropwise via an addition funnel after which thereaction was warmed to RT. The mixture was extracted with EtOAc and thecombined extracts washed sequentially with water and brine. The organicphase was dried (Na₂SO₄), filtered, and volatile solvents were removedin vacuo. The resulting solid was recrystallized from hexanes to afford3-chloro-5-methoxybenzonitrile (43, 4.2 g; 72%).

A 250 mL round bottom flask was charged with 43 (4.2 g; 25.05 mmol) and2,4,6-collidine (60 mL) was added. The mixture was stirred under anargon atmosphere until the solution was homogeneous. Anhydrous lithiumiodide (10.06 g; 75.18 mmol) was added and the mixture was heated to175° C. for 3 h. The reaction mixture was cooled to RT and partitionedbetween 10% HCl and EtOAc. The EtOAc phase was washed sequentially with10% HCl and brine, dried (Na₂SO₄), filtered and evaporated in vacuo toafford a oil which was crystallized from hexanes to afford3-chloro-5-hydroxybenzonitrile (44, 3.5 g, 91% theory).

To an ice-cold solution of 3-chloro-5-hydroxybenzonitrile (44; 3.5 g;22.80 mmol) and dry THF (50 mL) maintained under an argon atmosphere wasadded sodium tert-butoxide (2.2 g; 22.80 mmol) in two portions 15 minapart. The reaction mixture was stirred until the mixture washomogeneous. To the ice-cold solution was added dropwise2,3,4-trifluoronitrobenzene (4.0 g; 22.80 mmol) over 30 min. Thereaction was stirred at 0° C. for 3 h and then allowed to warm to RT.The reaction was cooled to 0° C. and quenched by addition of 10% HCl viaaddition funnel. The resulting mixture was extracted with EtOAc and thecombined organic phases washed sequentially with 10% HCl and brine. TheEtOAc was dried (Na₂SO₄), filtered and the volatile solvent removed invacuo to yield a yellow oil which was crystallized from hexanes to yield45 (6.3 g, 89% theory)

To an ice-cold solution of tert-butyl ethyl malonate (3.8 g; 20.28 mmol)and dry NMP maintained under an argon atmosphere was added NaH (1.2 g,48.67 mmol, 60% in mineral oil) over a 45 min interval. The reaction wasstirred for an additional 30 min after which 45 (6.3 g, 20.28 mmol) wasadded dropwise and the resulting solution stirred for 4 h. The reactionmixture was cooled to 0° C. and quenched by dropwise addition of asaturated NaHSO₄ solution. The mixture was extracted with EtOAc and thecombined organic extracts washed sequentially with water and brine. TheEtOAc solution was dried (Na₂SO₄), filtered and the volatile solventsremoved in vacuo to afford 46 as a purple oil that was used withoutfurther purification.

The crude mixed ester 46 from the previous step (8.9 g; 18.60 mmol) wasdissolved in DCM (100 mL) and 50 mL of TFA was added and the solutionwas to heated to 60° C. for 24 h. The reaction mixture was cooled to 0°C. and saturated NaHCO₃ was added dropwise to the stirred reactionmixture. The resulting solution was extracted with EtOAc and washedsequentially with saturated NaHCO₃, water and brine. The organic phasewas dried (Na₂SO₄), filter and the volatile solvents removed in vacuo.The resulting dark oil was crystallized from hexanes to afford 47 (6.5g, 92% theory).

To a solution of 47 (6.5 g; 17.20 mmol) and absolute EtOH (100 mL) wasadded NH₄Cl (1.84 g, 34.39 mmol) dissolved in water (20 mL). Theresulting mixture was heated at 60° C. until the reaction washomogeneous. Fe(0) (1.44 g, 25.80 mmol) was then added and the mixturestirred vigorously at 60° C. for 6 h. When reduction was complete thehot reaction mixture was filtered through a pad of CELITE® whichsubsequently was washed with hot EtOAc. The resulting filtrate wascooled and extracted with EtOAc and the combined extracts washedsequentially with water and brine. The EtOAc extract was dried (Na₂SO₄),filtered and the volatile solvent was removed in vacuo to afford a paleorange oil which was crystallized from hexanes to yield 48 (5.0 g, 83%theory).Introduction of 5-bromo Substituent

A 150 mL three-neck round bottom flask was charged with MeCN (50 mL),CuBr (2.8 g, 12.61 mmol) and t-butyl nitrite (1.4 g, 13.76 mmol),degassed and maintained under an Ar atmosphere and heated to 70° C. Tothe mixture was added dropwise a solution of 48 (4.0 g, 11.47 mmol)dissolved MeCN (20 mL). The reaction mixture was stirred at 70° C. for 4h and then cooled to 0° C. The reaction was quenched by addition of 10%HCl (30 mL) and extracted with EtOAc. The combined extracts weresequentially washed with 10% HCl and brine. The organic extract wasdried (Na2SO4), filtered and the volatile solvents removed in vacuo toyield a black oil which was purified by flash chromatography on silicagel (hexanes:EtOAc 95:5) to afford 49 (2.5 g, 52.8% theory).Introduction of 5-methyl Substituent

To a degassed ice-cold solution of THF (15 mL), Pd(dppf)Cl₂ (0.09 g,0.121 mmol) was added DIBAL-H (0.012 mmol; 1M in toluene). The reactionmixture was allowed to warm to RT. A solution of 49 (1.0 g, 2.42 mmol)was added followed by dimethyl zinc (1M in THF, 4.240 mmol). Thereaction was heated to 65° C. for 4 h, cooled to RT and quenched withaqueous NH₄Cl. The resulting mixture was extracted with EtOAc and washedsequentially with NH₄Cl and brine. The EtOAc extract was dried (Na₂SO₄),filtered and the volatile solvent removed in vacuo to yield a dark brownoil that was purified by flash chromatography on silica gel(hexanes:EtOAc 95:5) to yield 50 (0.50 g, 59% theory).Introduction of 5-ethyl Substituent

51 was prepared in by an identical procedure to 50 except diethylzincwas substituted for dimethyl zinc. The product was purified by flashchromatography on silica gel (hexanes:EtOAc 95:5) to yield 49 (0.65 g,74% theory).

Introduction of a pyridazinone into 49, 50 or 51 is carried out by thedeprotonation of the phenylacetic acid and condensation with3,6-dichloropyrazine as described in U.S. Ser. No. 10/807,993 (J. P.Dunn et al., U.S. Publication 20040198736.).

[4-Chloro-3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-phenyl]-aceticacid ethyl ester,[4-Bromo-3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-phenyl]-aceticacid ethyl ester,[3-(3-cyano-5-difluoromethyl-phenoxy)-2-fluoro-4-methyl-phenyl]-aceticacid ethyl ester and[3-(3-cyano-5-difluoromethyl-phenoxy)-4-ethyl-2-fluoro-phenyl]-aceticacid ethyl ester were prepared by a similar route except in step2,3-chloro, 5-hydroxy benzonitrile was replaced with3-difluoromethyl-5-hydroxy-benzonitrile. These compounds are usefulsynthetic intermediates for the synthesis of pyridazinone compounds.

The features disclosed in the foregoing description, or the followingclaims expressed in their specific forms or in terms of a means forperforming the disclosed function, or a method or process for attainingthe disclosed result, as appropriate, may, separately, or in anycombination of such features, be utilized for realizing the invention indiverse forms thereof.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1-9. (canceled)
 10. A compound according to formula Va wherein:

R² is an aryl radical and said aryl radical is optionally substitutedwith zero to three substituents independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ sulfonyl, C₁₋₆haloalkoxy, C₁₋₆ haloalkylthio, hydroxy, halogen, amino, C₁₋₆alkylamino, C₁₋₆ dialkylamino, aminoacyl, acyl, C₁₋₆ alkoxycarbonyl,carbamoyl, C₁₋₆N-alkylcarbamoyl, C₁₋₆N,N-dialkylcarbamoyl, nitro andcyano; R^(4a) is in each occurrence is independently hydrogen C₁₋₆alkyl, tert-butyl or benzyl; R⁵ is H or CO₂R^(5a): and R^(5a) isindependently in each occurrence a straight or branched C₁₋₆ alkyl
 11. Acompound according to formula Vb

wherein R² is an aryl radical and said aryl radical is optionallysubstituted with zero to three substituents independently selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆sulfonyl, C₁₋₆ haloalkoxy, C₁₋₆ haloalkylthio, hydroxy, halogen, amino,C₁₋₆ alkylamino, C₁₋₆ dialkylamino, aminoacyl, acyl, C₁₋₁₆alkoxycarbonyl, carbamoyl, C₁₋₆N-alkylcarbamoyl,C₁₋₆N,N-dialkylcarbamoyl, nitro and cyano; R^(4a) is hydrogen C₁₋₆alkyl, tert-butyl or benzyl; R⁶ is chloro, bromo or C₁₋₆ alkyl.